X-linked inhibitor of apoptosis protein (XIAP) possesses a critical role in promotion of cell survival and maintenance of cellular homeostasis. In cancer, elevated XIAP expression has been associated with malignancy, poor prognosis, and treatment resistance. However, the underlying mechanisms of these effects remain unclear. XIAP has previously been proposed to promote tumor growth through suppression of autophagy. In this study, we examined the expression of XIAP and p62, two critical mediators of autophagy, in breast and colon cancer. We observed a negative correlation between XIAP and p62 expression in normal and cancer tissues of breast and colon, and that the ratio of XIAP and p62 expression determines the cancer phenotype. In vitro, we observed that XIAP interacted with p62 and also that XIAP depletion resulted in increased expression of p62. XIAP functioned as an ubiquitination E3 ligase towards p62 and suppressed p62 expression through ubiquitin-proteasomal degradation. Furthermore, XIAP enhanced cancer cell proliferation, viability, and colony formation in vitro via suppression of p62. In addition, we demonstrated that XIAP-enhanced tumor growth is dependent on depletion of p62 in vivo. Herein, we have therefore delineated a novel mechanism by which XIAP contributes to development and progression of breast and colon carcinoma.